Abstract
New biological tools are required to understand the functional significance of genetic events revealed by whole genome sequencing (WGS) studies in oesophageal adenocarcinoma (OAC). The MFD-1 cell line was isolated from a 55-year-old male with OAC without recombinant-DNA transformation. Somatic genetic variations from MFD-1, tumour, normal oesophagus, and leucocytes were analysed with SNP6. WGS was performed in tumour and leucocytes. RNAseq was performed in MFD-1, and two classic OAC cell lines FLO1 and OE33. Transposase-accessible chromatin sequencing (ATAC-seq) was performed in MFD-1, OE33, and non-neoplastic HET1A cells. Functional studies were performed. MFD-1 had a high SNP genotype concordance with matched germline/tumour. Parental tumour and MFD-1 carried four somatically acquired mutations in three recurrent mutated genes in OAC: TP53, ABCB1 and SEMA5A, not present in FLO-1 or OE33. MFD-1 displayed high expression of epithelial and glandular markers and a unique fingerprint of open chromatin. MFD-1 was tumorigenic in SCID mouse and proliferative and invasive in 3D cultures. The clinical utility of whole genome sequencing projects will be delivered using accurate model systems to develop molecular-phenotype therapeutics. We have described the first such system to arise from the oesophageal International Cancer Genome Consortium project.
Highlights
There is a paucity of such tools with which to study oesophageal adenocarcinoma (OAC)
We show that MFD-1 is a highly representative model of OAC, it is stable over time and retains the ability to form tumours in xenograft models that respond to microenvironmental stimuli
This deficiency is frustrating efforts to understand the basic biology of progression to OAC and the development of novel therapies for established cancer[7]
Summary
There is a paucity of such tools with which to study OAC. This lack of suitable preclinical models is frustrating efforts to understand both the basic biology of the transition from BE to OAC and the development of novel therapies for established cancer[7]. Well-described and authenticated, cell lines derived from OAC without any in-vitro modification are valuable tools, such as the recently introduced OANC114,15. These cell lines may or may not be representative of the mutational profile of cells driving the malignancy in vivo[16]. Using complementary genome wide analysis techniques including whole genome sequencing and genotyping of tumour biopsy and matched normal tissue from the oesophagus and peripheral blood we describe the establishment of a new model system in OAC (MFD-1) that retains the mutational profile of the primary tumour, including the identification of novel mutations in recognised cancer associated genes in OAC. We show that MFD-1 is a highly representative model of OAC, it is stable over time and retains the ability to form tumours in xenograft models that respond to microenvironmental stimuli
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